Reproductive immunology

Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus. Erlebacher, A. et al. J. Clin. Invest. 117, 1399–1411 (2007)

Why does the maternal immune system not recognize the fetus as foreign? Determining how fetal antigens are presented to maternal T cells might hold the answer. In this paper, the authors developed a system to visualize T-cell responses to the fetus, and found that fetal antigens are presented to both maternal CD4+ and CD8+ T cells exclusively through indirect antigen presentation. This pathway of presentation ensures that the large population of T cells that are activated by direct presentation and that typically drive acute transplantation rejection are unaware of the fetal allograft. In addition, defective priming and clonal deletion of CD8+ T cells was observed following exposure to fetal antigens, and antigen presentation commenced only at mid-gestation. So, by limiting how maternal T cells recognize fetal antigens, the fetus can escape rejection by the maternal immune system.

Evolution

Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Rogozin, I. B. et al. Nature Immunol. 29 April 2007 (doi:10.1038/ni1463)

Jawless vertebrates, including lampreys and hagfish, do not have immunoglobulins but instead have variable lymphocyte receptors (VLRs). VLRs are somatically rearranged receptors composed of diverse leucine-rich repeats but the mechanism of their assembly is not known. Here, Rogozin and colleagues assembled a draft of the sea lamprey genome. Comparison of genomic sequences with mature VLR sequences revealed that mature VLRs are assembled from multiple genomic cassettes in a gene-conversion-like process. The authors also identified genes encoding two members of the AID-APOBEC cytosine deaminase family and found that these putative deaminases might be involved in VLR diversification and could therefore represent a primordial mechanism of the AID-induced DNA strand breaks that are required for immunoglobulin gene conversion.

T-cell development

RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. Rossi, S. W. et al. J. Exp. Med. 14 May 2007 (doi:10.1084/jem.20062497)

Central tolerance occurs in the thymus when developing thymocytes interact with specialized medullary thymic epithelial cells (mTECs) which express autoimmune regulator (AIRE), a transcription factor that controls the expression of tissue-restricted antigens by mTECs. To date, the molecular mechanisms controlling mTEC development have been undefined. Now, Rossi and colleagues show that CD4+CD3− lymphoid-tissue inducer cells — which have previously been associated with the development and function of secondary lymphoid tissue — are present in the thymus and express the RANK (receptor activator of nuclear factor-κB) ligand. These cells control the development of mature AIRE+ mTECs from RANK+AIRE− mTEC progenitor cells. When RANK− thymic stromal cells were transplanted into immunodeficient hosts, this resulted in autoimmunity similar to the disease that occurs when AIRE is defective, confirming a key role for RANK as a regulator of central tolerance.